Application of Molecular Dynamics to the Investigation of Metalloproteins Involved in Metal Homeostasis

Sala, Davide; Musiani, Francesco; Rosato, Antonio

doi:10.1002/ejic.201800602

Cited by 13 publications

(9 citation statements)

References 205 publications

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“…is a challenging task and a currently active research topic. − Modeling strategies for metals in protein simulations (including the nonbonded, bonded, cationic dummy atom, and combined models) have been recently reviewed in ref . Some examples of the application of these models to the zinc(II) ion have been listed in ref . The salient differences of the various modeling approaches are related to the description of the interactions between the metal cation and the protein residues that bind the metal.…”

Section: Introductionmentioning

confidence: 99%

Upgrading and Validation of the AMBER Force Field for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with Four Protein Ligands

Macchiagodena

Pagliai

Andreini

et al. 2019

J. Chem. Inf. Model.

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We developed and validated a novel force field in the context of the AMBER parameterization for the simulation of zinc(II)-binding proteins. The proposed force field assumes nonbonded spherical interactions between the central zinc(II) and the coordinating residues. A crucial innovative aspect of our approach is to account for the polarization effects of the cation by redefining the atomic charges of the coordinating residues and an adjustment of Lennard-Jones parameters of Zn-interacting atoms to reproduce mean distance distributions. The optimal transferable parametrization was obtained by performing accurate quantum mechanical calculations on a training set of high-quality protein structures, encompassing the most common folds of zinc(II) sites. The addressed sites contain a zinc(II) ion tetra-coordinated by histidine and cysteine residues and represent about 70% of all physiologically relevant zinc(II) sites in the Protein Data Bank. Molecular dynamics simulations with explicit solvent, carried out on several zinc(II)-binding proteins not included in the training set, show that our model for zinc(II) sites preserves the tetra-coordination of the metal site with remarkable stability, yielding zinc(II)−X mean distances similar to experimental data. Finally, the model was tested by evaluating the zinc(II)-binding affinities, using the alchemical free energy perturbation approach. The calculated dissociation constants correlate satisfactorily with the experimental counterpart demonstrating the validity and transferability of the proposed parameterization for zinc(II)-binding proteins.

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Section: Introductionmentioning

confidence: 99%

Upgrading and Validation of the AMBER Force Field for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with Four Protein Ligands

Macchiagodena

Pagliai

Andreini

et al. 2019

J. Chem. Inf. Model.

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“…The mechanism by which the Ni(II) ion interacts with SyInrS, which in principle can occur through an induced fit mechanism, a conformation selection in solution, or a combination of both, is far from being fully understood. To this aim, InrS and the other members of the RcnR/CsoR family can be interesting targets for further computational studies aimed to the exploration of the conformational space of these proteins through molecular dynamics techniques, as recently proposed by some of us [36]. On the other hand, the study of the Ni(II) bound form of SyInrS requires the development of specific force field parameters able to model a Ni(II) ion in the square planar coordination.…”

Section: Discussionmentioning

confidence: 99%

Molecular Modelling of the Ni(II)-Responsive Synechocystis PCC 6803 Transcriptional Regulator InrS in the Metal Bound Form

Barchi

Musiani

2019

Inorganics

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InrS (internal nickel-responsive sensor) is a transcriptional regulator found in cyanobacteria that represses the transcription of the nickel exporter NrsD in the apo form and de-represses expression of the exporter upon Ni(II) binding. Although a crystal structure of apo-InrS from Synechocystis PCC 6803 has been reported, no structure of the protein with metal ions bound is available. Here we report the results of a computational study aimed to reconstruct the metal binding site by taking advantage of recent X-ray absorption spectroscopy (XAS) data and to envisage the structural rearrangements occurring upon Ni(II) binding. The modelled Ni(II) binding site shows a square planar geometry consistent with experimental data. The structural details of the conformational changes occurring upon metal binding are also discussed in the framework of trying to rationalize the different affinity of the apo- and holo-forms of the protein for DNA.

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“…It is estimated that 25-40% of all proteins are metalloproteins. [1][2][3] Ca 2+ is a second messenger inside cells, [4][5][6] and Ca 2+ -binding proteins are critical in a variety of cellular processes involved in cell growth, muscle contractions, cell signaling, and transcription factor regulation. 7 For example, the S100 Ca 2+ -binding protein family plays important roles in cancer development.…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into the Calcium Binding in Troponin C Through a Molecular Dynamics Study

Smith

2022

Preprint

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Calcium-binding proteins play critical roles in various biological processes such as signal transduction, cell growth, and transcription factor regulation. Ion binding and target binding of Ca2+-binding proteins are highly related. Therefore, understanding the ion binding mechanism will benefit the relevant inhibitor design towards the Ca2+ binding proteins. The EF-hand is the typical ion binding motif in Ca2+-binding proteins. Previous studies indicate that the ion binding affinity of the EF-hand increases with peptide length, but this mechanism has not been fully established. Herein, using molecular dynamics (MD) simulations, thermodynamic integration (TI) calculations, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) analysis, we systematically investigated four Ca2+ binding peptides containing the EF-hand loop in the site III of rabbit skeletal troponin C (TnC). These four peptides have 13, 21, 26, and 34 residues, respectively. Our simulations reproduced the observed trend that the ion binding affinity increases with peptide length. Our results implied that the E-helix motif preceding the EF-hand loop, especially the Phe99 residue, plays a significant role in this regulation. The E-helix has a significant impact on the backbone and sidechain conformations of the Asp103 residue, rigidifying important hydrogen bonds in the EF-hand and decreasing the solvent exposure of the Ca2+ ion, hence leading to more favorable Ca2+ binding in longer peptides. The present study provides molecular insights into the ion binding in the EF-hand and establishes an important step towards elucidating the responses of Ca2+-binding proteins towards the ion and target availability.

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Application of Molecular Dynamics to the Investigation of Metalloproteins Involved in Metal Homeostasis

Cited by 13 publications

References 205 publications

Upgrading and Validation of the AMBER Force Field for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with Four Protein Ligands

Upgrading and Validation of the AMBER Force Field for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with Four Protein Ligands

Molecular Modelling of the Ni(II)-Responsive Synechocystis PCC 6803 Transcriptional Regulator InrS in the Metal Bound Form

Molecular Insights into the Calcium Binding in Troponin C Through a Molecular Dynamics Study

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